Basal Ganglia Local Field Potentials as a Potential Biomarker for Sleep Disturbance in Parkinson's Disease

Abstract

Sleep disturbances, specifically decreases in total sleep time and sleep efficiency as well as increased sleep onset latency and wakefulness after sleep onset, are highly prevalent in patients with Parkinson's disease (PD). Impairment of sleep significantly and adversely impacts several comorbidities in this patient population, including cognition, mood, and quality of life. Sleep disturbances and other non-motor symptoms of PD have come to the fore as the effectiveness of advanced therapies such as deep brain stimulation (DBS) optimally manage the motor symptoms. Although some studies have suggested that DBS provides benefit for sleep disturbances in PD, the mechanisms by which this might occur, as well as the optimal stimulation parameters for treating sleep dysfunction, remain unknown. In patients treated with DBS, electrophysiologic recording from the stimulating electrode, in the form of local field potentials (LFPs), has led to the identification of several findings associated with both motor and non-motor symptoms including sleep. For example, beta frequency (13-30 Hz) oscillations are associated with worsened bradykinesia while awake and decrease during non-rapid eye movement sleep. LFP investigation of sleep has largely focused on the subthalamic nucleus (STN), though corresponding oscillatory activity has been found in the globus pallidus internus (GPi) and thalamus as well. LFPs are increasingly being recognized as a potential biomarker for sleep states in PD, which may allow for closed-loop optimization of DBS parameters to treat sleep disturbances in this population. In this review, we discuss the relationship between LFP oscillations in STN and the sleep architecture of PD patients, current trends in utilizing DBS to treat sleep disturbance, and future directions for research. In particular, we highlight the capability of novel technologies to capture and record LFP data in vivo, while patients continue therapeutic stimulation for motor symptoms. These technological advances may soon allow for real-time adaptive stimulation to treat sleep disturbances.

Keywords: Parkinson's disease; biomarker; deep brain stimulation (DBS); local field potential (LFP); sleep.

Figure 1

(A) Relative frequency contribution of each spectral band to different sleep stages. There exist shared sleep-stage dependent spectral patterns across subjects, although with some notable across-subject variability. Each individual plot highlights the distribution of the power of a given frequency band to different stages of sleep for 10 different subjects. In the awake state (red), power is highest in the beta and gamma frequencies, while NREM sleep (blue) is dominated by lower frequencies (delta, theta, and alpha). REM sleep (green) exhibits the greatest variability in representation across the frequency spectra [adapted from (73)]. (B) Distribution of frequency band power contribution to sleep stage for a cohort of nine subjects. AWM, awake with movement; AWOM, awake without movement; REM, rapid eye movement; N1–3, non-rapid eye movement stages 1–3 [adapted from (75)].

Figure 2

(A) Representative spectrogram of a LFP recording acquired over the course of one full night's sleep from a DBS electrode implanted into the STN. A PSG-informed hypnogram assessed by a sleep expert is aligned with the LFP recordings (red line). AWM, awake with movement; AWOM, awake without movement; REM, rapid eye movement; N1–3, non-rapid eye movement stages 1–3. (B) Comparison of hypnogram assessed by a sleep expert (top; black) and ANN-predicted hypnogram (bottom; red) from a single patient. R, rapid eye movement; N, non-rapid eye movement; A, awake [adapted from (75)].

Figure 3

Potential DBS targets for treatment of sleep dysfunction in PD. STN DBS may increase total sleep time and sleep efficiency, reduce wakefulness after sleep onset, and in some studies, increase REM duration. GPi DBS may improve sleep quality and daytime sleepiness. A single study in five PD patients with GPi DBS demonstrated a non-statistically significant increase sleep quality and efficiency, with decreased WASO, sleep onset latency, and REM latency. GPe DBS may improve insomnia and improve sleep efficiency. PPN DBS may improve sleep efficiency, REM duration, and daytime sleepiness, and decrease WASO. The ascending arousal system (orange arrows) sends projections from the brainstem and posterior hypothalamus throughout the forebrain (116). Neurons of the laterodorsal tegmental nuclei and PPN send cholinergic fibers to many forebrain targets, including the thalamus, which then regulate cortical activity. Aminergic nuclei diffusely project throughout much of the forebrain, regulating the activity of cortical and hypothalamic targets directly. These include neurons of the tuberomammillary nucleus containing histamine, neurons of the dorsal raphe nuclei containing 5-HT, and neurons of the locus coeruleus containing noradrenaline. TMN, tuberomammillary nucleus; DRN, dorsal raphe nucleus; LC, locus coeruleus (117, 118).

Figure 4

Schematic illustration of an adaptive closed-loop DBS system used to treat sleep dysfunction. LFPs are detected by the DBS lead. With integrated classifiers, sleep stages are predicted, and closed-loop algorithms can adjust the DBS pulses. For example, stimulation amplitude may be decreased during certain sleep stages where beta frequency power is lower [modified from (74)].